The increasing prevalence of obesity in this country has grave public health implications due to associated diseases and complications. Despite increasing evidence that obesity is a genetic disorder with inherent abnormalities in insulin-stimulated fuel metabolism, virtually nothing is known about the nature of early metabolic defects and the antecedents of obesity-related complications in children at high risk for adult obesity. In the present study, we will examine these questions by performing comprehensive metabolic and clinical assessments in lean and obese preadolescent children of parents who are both affected with abnormal obesity. The euglycemic, hyperinsulinemic clamp technique will be used in combination with stable isotopic tracer infusions and indirect calorimetry to identify defects in insulin-stimulated glucose, amino acid and lipid metabolism. The hyperglycemic clamp will be used to detect alterations in glucose-stimulated insulin responses. Results in the high risk children will be compared with those in lean preadolescents of nonobese parents, subjects who are normally exquisitely sensitive to insulin and who have the lowest insulin responses to glucose. Metabolic defects in the at risk population will be related to alterations in fat distribution assessed by MRI techniques. Each group will be prospectively followed into adolescence in order to determine the evolution of the metabolic abnormalities and how they are related to accumulation and distribution of body fat and the development of changes in blood pressure and circulating lipids. In summary, these studies will provide new important data on the mechanisms underlying the development of obesity in humans.